title: ZAC1 and SSTR2 are downregulated in non-functioning pituitary adenomas but not in somatotropinomas.
abstract: BACKGROUND
  There are few data regarding ZAC1 expression in clinically non-functioning pituitary adenomas (NFPA). Because somatotropinomas and NFPA behave differently with respect to tumor shrinkage during somatostatin analogs (SA) therapy, we sought to compare the ZAC1 and somatostatin receptor (sstr) types 1, 2, 3 and 5 mRNA expression in these two pituitary adenoma subtypes and in normal human pituitaries.
  
  
  METHODS
  ZAC1 and SSTR mRNA expression levels were evaluated using real-time RT-PCR (TaqMan) in 20 NFPA and compared with the expression levels in 23 somatotropinomas and five normal pituitaries. The NFPA invasiveness was evaluated using magnetic resonance imaging with Hardy's modified criteria. Ki-67 and p53 were evaluated using immunohistochemistry.
  
  
  RESULTS
  A total of 20 patients with NFPA [6 males, median age 56 years (range: 30-78)], 23 with acromegaly [12 males, median age 43 years (range: 24-57)] and five normal pituitaries [4 males, median age 48 years (range: 36-54)] were included. Four of the patients (20%) had Hardy's grade 2 tumors; all of the others had Hardy's grade 3 tumors. The Ki-67 median expression was 2.35 (range: 0.2-9.23), and only four of the tumors (20%) were positive for p53. The ZAC1 mRNA expression was significantly lower in NFPA than in somatotropinomas and in normal pituitaries (p<0.001 for both), as well as the SSTR2 (p=0.001 and 0.01, respectively). The SSTR3 expression was higher in the NFPA than in the somatotropinomas and in the normal pituitaries (p=0.03 and 0.02, respectively). No correlation was found between the ZAC1 mRNA expression and the tumor invasiveness, Ki-67 and p53.
  
  
  CONCLUSIONS
  ZAC1 and SSTR2 are underexpressed and SSTR3 is overexpressed in NFPA compared to those in somatotropinomas and in normal pituitaries, which might explain the lack of tumor shrinkage that is observed in response to commercially available SA therapy in patients with NFPA.
authors.affiliation: Department of Internal Medicine and Endocrine Unit, Medical School and Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil ; Endocrinology Unit, Federal Hospital of Lagoa, Rio de Janeiro, Brazil.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Vieria Neto
authors.forename: Luiz Eduardo
authors.initials: LE
authors.lastname: Wildemberg
authors.forename: Leandro Machado
authors.initials: LM
authors.lastname: Colli
authors.forename: Leandro
authors.initials: L
authors.lastname: Kasuki
authors.forename: Nelma Veronica
authors.initials: NV
authors.lastname: Marques
authors.forename: Aline Barbosa
authors.initials: AB
authors.lastname: Moraes
authors.forename: Emerson L
authors.initials: EL
authors.lastname: Gasparetto
authors.forename: Christina Maeda
authors.initials: CM
authors.lastname: Takiya
authors.forename: Margaret
authors.initials: M
authors.lastname: Castro
authors.forename: Mônica Roberto
authors.initials: MR
authors.lastname: Gadelha
mesh_terms: D000236:Adenoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen; C106464:PLAGL1 protein, human; D017481:Receptors, Somatostatin; C574734:SSTR2 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C103631:somatostatin receptor 3; C101130:somatostatin receptor type 1; D013004:Somatostatin; C094573:somatostatin receptor 5